The human immunodeficiency virus (“HIV”) is the causative agent for acquired immunodeficiency syndrome (“AIDS”), a disease characterized by the destruction of the immune system, particularly of CD4 T-cells with susceptibility to opportunistic infections. In nearly all cases where individuals receive no treatment for HIV infection, the proliferation of the virus gives rise to AIDS. As of early 1999, an estimated 33.4 million people are infected with HIV worldwide. Furthermore, in 2009 approximately 50,000 people were newly infected with HIV in the United States [Prejean J, Song R, Hernandez A, et al. Estimated HIV incidence in the United States, 2006-2009. PLoS ONE 2011; 6(8): e7502]. It has also been observed that the annual rate of new infection with HIV in the entire human population has not declined. Despite this fact, the rate of death due to AIDS has begun to drop in some nations primarily through the recent use of combination drug therapies against HIV infection.
The means by which such therapies counter HIV infection is best understood with reference to the biological mechanisms of the HIV life cycle. HIV is a member of a class of infectious agents known as retroviruses. The infectious form of HIV, a virion, is a particle that consists of a viral genome composed of RNA that is surrounded by proteins encoded by the genome. Infection occurs when an HIV virion enters a susceptible host cell, such as a T lymphocyte within the bloodstream. At this point, one of the viral proteins that comprise the virion, reverse transcriptase (RT), synthesizes a double-stranded DNA copy of the HIV RNA genome. The resulting HIV DNA enters the cell nucleus as part of a stable complex with other virion proteins. This complex contains all the necessary molecular apparatus for integration wherein the HIV DNA is covalently inserted into the host cell's genomic DNA which is absolutely required for prolific HIV infection. It is only after integration that the HIV DNA can serve as the template for the production of HIV proteins and RNA that will comprise progeny virions. Among these viral proteins is the HIV protease, the activity of which is necessary for proper formation of new virions. This process, from viral entry to new virion production, is termed viral replication. Upon release from an infected host cell, the newly produced virions are capable of further infecting uninfected host cells. It is through successive rounds of HIV replication and productive host cell infection that HIV disease spreads throughout numerous host cells and ultimately progresses to AIDS.
The current strategy recommended for the treatment of HIV infection is Highly Active Antiretroviral Therapy (HAART). HAART normally consists of a combination of antiretroviral drugs (ARV) taken together. These therapies consist of simultaneous or separate administration of combination of drugs, which potently and selectively target different elements of the HIV life cycle to disrupt or forestall productive HIV infection and progression to AIDS.
For example WO2008043829 discloses a method of treating HIV wherein emtricitabine, tenofovir and nevirapine are administered once a day.
WO04087169 discloses a composition useful for the treatment or prophylaxis of viral infections comprising nevirapine and at least one antiviral active compound such as alovudine.
US20100183716 discloses compressed tablets containing atazanavir sulfate, optionally with another active agents, e.g., anti-HIV agents, granules that contain atazanavir sulfate and an intragranular lubricant that can be used to make the tablets, compositions comprising a plurality of the granules, processes for making the granules and tablets, and methods of treating HIV.
WO2011127244 discloses compressed tablets containing atazanavir sulfate and an acidifying agent, optionally with another active agent, e.g., anti-HIV agents.
U.S. Pat. No. 7,432,294 disclose composition comprising one or more solubilized HIV protease inhibiting compounds with other HIV protease inhibiting compound.
EP1083932 discloses homogeneous combination of abacavir, lamivudine, and zidovudine in an amount which achieves antiviral efficacy.
Although the use of combination drug therapies against HIV has proven to be effective in many patients, the current drug regimens are far from ideal. Treatment failure often (though not always) occurs because a patient's strain of HIV may develop resistance to one or more of antiretroviral medications. The manner by which HIV develops resistance to antiretroviral drugs is similar to the way in which bacteria or mycobacterium develops resistance to antibiotics: for example election of insufficiently potent drug therapy for mutant strains that are resistant to the medications administered to the patient. These mutant strains then replace the wild-type strain due to their selective replication advantage in the face of drug pressure, leading to treatment failure.
Further the success of HAART depends on patient related factors as well, the most important being adherence. The HIV therapy is a life-long therapy coupled with high levels of adherence to the same. This is rather a demanding task for HIV infected patients due to various reasons such as low morale, social stigma, low immunity attributed to the disease. Some studies have also shown that adherence to prescribed drugs over long treatment periods is generally poor. (Jintanat A. et al. Swiss HIV Cohort Study. Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial AIDS, 2003; 17:F33-F37).
Hence, such non-adherence may lead to rebound in viral replication and, in presence of sub-optimal drug concentration may lead to rapid development of drug resistance. This development of drug resistance may be disastrous because of the complexity and cost associated with second line regimens and the potential for transmission of drug resistant virus in the community.
The therapy may involve use of different drug combinations, which are difficult to adhere, because of the different dosage forms for administering each such antiretroviral drug separately. This is of particular importance in the case of elderly patients.
Further for most of the therapeutic agents to produce systemic effects, the oral route still represents the preferred way of administration, owing to its several advantages and high patient compliance as compared to any other route of administration. Tablets and hard gelatin capsules still constitute a major portion of drug delivery systems that are currently available.
However, many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing the dosage forms such as tablets and hard gelatin capsules. Further, those who are traveling or have little access to water are similarly affected.
Also, the route of drug administration, appearance, color, taste, tablet size and dosing regimen are most important parameters that govern patient compliance.
Especially, the geriatric and paediatric patients experience difficulty in swallowing larger sized tablets wherein large size tablet may result in esophageal damage due to its physical characteristics if it is not swallowed properly, which ultimately leads to poor patient compliance.
Also, oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for paediatric patients.
Further, there has been an enhanced demand for dosage forms that are more patient-friendly and patient compliant. Since the development cost of a new drug molecule is very high, efforts are now being made to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency as well as which are cost-effective.
Although different treatment methods and dosage regimens have been framed in order to increase the patient adherence for treatment of HIV, there still remains a critical need for developing improved dosage forms such as a kit composition or dosage form by which a patient is encouraged to adhere to his daily dosage regimen. The combination of antiretroviral drugs administered in a single unit dosage form may result in increased patient compliance as the pill burden is reduced and dosing schedules are simplified. However, not all compounds are suitable for administration in combinations as there are several factors that influence the feasibility of combinations such as the chemical instability of the compounds, size of the dosage unit, potential for antagonistic or merely additive activities of the combined compounds, and difficulties in achieving a suitable formulation.
Thus there is an unmet need to find therapeutic agents suitable for use in combination to provide suitable pharmaceutical compositions to treat HIV infection and simultaneously increase the patient compliance.